The lung is a complex organ with the primary function of allowing the exchange of gasses between the body fluids and the external environment. The constant exposure to toxins makes the pulmonary epithelial cells highly susceptible to oncogenic transformation, leading to the development of lung cancer. This is borne by the fact that lung cancer is the leading cause of cancer related death in both sexes in the United States. The establishment of mutant mice that mimic the lung cancer will aid in the understanding of the molecular mechanisms regulating the development of this disease as well as aid in the development of means of early detection and the treatment of this disease. Modeling lung cancer in mice is not a simple task. Lung cancer is not one distinct disease but can be divided into four major, histologically identifiable subtypes [eI-Torky, 1990 #3]. These subtypes are adenocarcinoma, squamous cell carcinoma, small cell carcinoma, and large cell carcinoma. Currently, squamous cell carcinoma and adenocarcinoma are the most common type of lung cancer in the United States with adenocarcinoma being the most common form of lung cancer in women. In fact adenocarcinoma has increased to 45% of bronchogenic carcinomas with declines in squamous and large cell carcinomas, while small cell has remained at 20%. The goal of this MMHCC application is to develop mouse models for adenocarcinoma of the lung by creating genetic modifications that disrupt specific genes or pathways that have been associated with human lung cancer. These modifications will be targeted to one specific cell type of the mouse airways, the Clara cell. Once these progressions of cancer in these models have been characterized, the role inflammation plays in the progression of cancer in these models will be determined. The analysis of these models includes state of the art imaging and DNA and proteomic analysis of the molecular changes during cancer progression.